Studies toward the enantioselective total synthesis of (-)-cochleamycin A

by Chang, Jiyoung

Abstract (Summary)

A synthetic approach to the tricyclic ring system of the unnatural enantiomer of cochleamycin A is described. An (E,Z,E)-1,6,8-nonatriene was prepared by coupling two building blocks synthesized from L-(-)-malic and L-(-)-ascorbic acids, respectively. A highly enantioselective synthesis of the fully functionalized AB ring system was achieved by a stereocontrolled intramolecular Diels-Alder reaction that proceeds via an endo transition state. The resulting cis-tetrahydroindane system was examined for its potential along two flexible pathways to construct the CD ring system. Formation of the ten-membered carbocycle was initially explored. Different cyclization methods including the Nozaki-Hiyama-Kishi reaction, ring-closing olefin metathesis, and the Ramberg-Backlund rearrangement were not effective. As an alternative way, ten-membered macrolactone formation was also investigated. C ring formation was achieved by the Yamaguchi macrolactonization protocol. Attempts to complete the D ring system of the target molecule involving reductive cyclization of bromo lactone with a Weinreb amide were unsuccessful. The Nozaki-Hiyama-Kishi reaction of bromo aldehyde 4.27 proved to be unreliable. In one instance, HRMS data was obtained indicating the possible formation of a very small amount of the target tetracyclic system. However, this observation could not be reproduced.